Small Animal Ophthalmology

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Feline Herpesvirus Ocular Disease

Mark P. Nasisse, DVM*

Feline herpesvirus 1 (FHV-1, feline rhinotracheitis virus) is a DNA virus of the subfamily alphaherpesvirinae. Characteristics common to this group are rapid propagation of virus and destruction of cells in tissue culture, and the tendency to establish latency primarily, but not exclusively, in sensory ganglia following primary infection. Other animal viruses belonging to this subfamily include equine herpesvirus 1, suid herpesvirus 1, and bovine herpesvirus 2. The typical herpesvirus virion consists of a viral DNA core contained within an icosadeltahedral capsid. Abutting the capsid is an electron-dense material called the integument. The viral envelope, derived from the nuclear membrane of the host cell of origin, is the final structure comprising the virion. Epidemiologic studies indicate that as many as 50-75% of cats have serologic evidence of exposure to the virus. 13 · 48 · 50 Transmission occurs by direct contact between susceptible and infected cats, 19 with the severity of the infection determined in part by the inoculum of infecting virus and the immune status of the animal. 17

VIRAL PATHOGENESIS Upon primary exposure to FHV-1, rapid virus replication occurs in the epithelium of the upper respiratory tract, particularly the nasal epithelium and turbinates. 28 Ocular infection is characterized by a pronounced tropism for conjunctival epithelium; for unexplained reasons, FHV-1 replicates to a limited extent in epithelium of the cornea. 38 The virion gains access to the cell by first attaching to receptors on the epithelial cell surface. The viral envelope fuses to the host cell plasma membrane and the capsid is released into the cytoplasm. The viral DNA penetrates the cell nucleus, where it quickly controls cellular metabolic functions and directs the *Diplomate, American College of Veterinary Ophthalmologists; Associate Professor of Ophthalmology, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina Veterinary Clinics of North America: Small Animal Practice-Vol. 20, No. 3, May 1990

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synthesis of viral proteins. Lysis of the infected cell ensues as new infective virions that are assembled are released. Experimental studies have demonstrated that during primary FHV-1 infection, necrosis of susceptible epithelium occurs within 2 days, peaking between 7-10 days of infection. 28 Intranuclear viral inclusions are numerous and easily detected in histologic sections of affected tissue. Cellular necrosis is accompanied by a polymorphonuclear inflammatory response that is evident by day 3 of infection. A mononuclear infiltrate does not become apparent until several days later. Infection quickly runs its course, and rapid epithelial cell regeneration begins between days 7 and 10. Virus shedding in ocular and nasal secretions may be detected as early as day 2 of infection and has usually ended by day 20.

FELINE HERPESVIRUS 1 LATENCY It has long been recognized that FHV-1 can establish latency following primary infection. The incidence of latent infection, as measured by virus shedding following pharmacologic immunosuppression, is estimated at 80%. 20 It is quite possible, however, that more sensitive means of identifying latent virus, such as in situ hybridization of tissue with viral-specific DNA probes, 47 will reveal an even higher incidence of latent infection. Because most members of the alphaherpesvirinae subfamily establish latency in sensory ganglia, it has long been suspected that FHV-1 does also. The subject has remained controversial, however, because the traditional tissueculture techniques of cocultivation and explant culture have failed to recover virus from trigeminal ganglia oflatently infected cats in numerous studies. 14 • 18 · 43 That FHV-1 could establish latency in trigeminal ganglia was demonstrated in a 1985 report describing the successful isolation of FHV-1 by explant culture techniques from the ganglia of 3 of 17 latently infected cats. 21 Using a similar technique to investigate ganglionic latency following experimental ocular infection, we have demonstrated a similar isolation rate; trigeminal ganglia from 4 of 20 cats yielded FHV-1 (Nasisse, unpublished data). It is probable, however, that this low incidence reflects only the limited ability of these tissue-culture methods to reactivate latent FHV-1. Recent studies of other herpesviruses indicate that latent infection may occur in other tissues, namely corneal epithelial and stromal cells. 1• 45 A relationship, however, between corneal latency and ocular disease has not been established. Although the subject of continued investigation, most evidence to date suggests there is limited transcription of latent herpesviruses. The factors responsible for reactivation oflatent virus likewise remain to be determined. For FHV-1, reactivation oflatent virus is associated with natural or artificial stress factors such as lactation, overcrowding, and corticosteroid administration. Of the 80% of cats known to become latently infected following primary infection, it is estimated that the virus will reactivate and shed spontaneously in nearly half. 2° For virus latent in the trigeminal ganglia, reactivation and centripetal spread along the nerve's axons to the affected

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eye constitutes the round-trip theory, by which recrudescent ocular infections are presumed to occur.

THE IMMUNE RESPONSE TO FELINE HERPESVIRUS 1 INFECTION The first line of defense to herpesvirus infections is generally considered to be dependent on macrophages, in cooperation with natural killer cells and interferon. 32 In vitro studies have demonstrated that lysis of FHV-1-infected cells occurs through antibody and complement, antibodydependent cell-mediated lysis, and direct cytotoxicity, presumably by T lymphocytes. 24 • 50 A delayed-type hypersentivitity reaction has also been demonstrated in the skin of previously sensitized cats; 49 the significance of this to ocular disease is uncertain, however. A serologic response following FHV-1 exposure is of low magnitude (titers of 1:16 to 1:32) and is first measurable between postinfection days 12 and 16. u Viral glycoproteins have recently been shown to be the major antigens inducing the humoral immune response .8 Serum neutralizing antibodies increase after reinfection, but tend to remain constant thereafter. Immunity to FHV-1 is incomplete in the sense that neither natural nor vaccinational immunity prevents reinfection. It is estimated that cats are susceptible to reinfection within 6 months of the primary infection. Vaccination immunity reduces the severity of clinical signs but does not prevent infection. 5 · 6 • 10• 30• 39 Intranasal vaccination, however, has been shown to limit the establishment oflatency. 39 Immunosuppressive disorders, whether naturally occurring or iatrogenic, are considered to aggravate the severity of clinical signs associated with FHV-1 infection. A correlation between feline leukemia virus and, more recently, feline immunodeficiency virus infection and chronic FHV-1 infection has been suggested. 3• 55 A profound negative effect of ocularly administered corticosteroids on the course and severity of primary ocular infection has recently been described.38

CLINICAL MANIFESTATIONS OF FELINE HERPESVIRUS 1 INFECTION Acute Infection The majority of acute FHV-1 infections occur in neonatal ~nd young adult cats. In such cases, upper respiratory signs predominate, with sneezing and nasal and ocular discharge being the typical clinical signs. In cats able to mount an appropriate immune response, the infection is selflimiting, with resolution of clinical signs in 14-20 days. The reader is referred to one of several recent reviews for a more detailed discussion of the systemic manifestations of FHV-1 infection. 2 • 22 The ocular manifestations of acute FHV-1 infection are nearly always bilateral, and conspicuous clinical signs are generally limited to the con-

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junctiva. In experimental infection, blepharospasm is the initial clinical sign, beginning several days postinoculation and peaking by day 5, when it is accompanied by serous ocular discharge. Ocular discharge becomes mucoid to mucopurulent by day 7 but begins to subside by day 10. The conjunctival appearance in acute infection is that of extreme hyperemia (Fig. 1). Mild conjunctival swelling is present, but chemosis is not a conspicuous feature of FHV-1 infection. The conjunctival lesions represent the direct cytolytic effects of FHV-1 infection. Histologic evaluation of infected conjunctiva at day 4 of infection reveals diffuse conjunctival necrosis and the ubiquitous presence of intranuclear inclusions within epithelial cells, with a minimum number of inflammatory cells. By day 8 of experimental infection, conjunctival necrosis is severe and accompanied by sloughing of epithelium. Conjunctival necrosis, by this time, is associated with a massive polymorphonuclear cell response; macrophages are less numerous (Fig. 2). Corneal infection does occur during primary ocular FHV-1 infection, but reflecting the marked tropism of this virus for conjunctival epithelium, corneal lesions are far less conspicuous. Corneal dendritic (branch-like) figures are seen in a biphasic pattern during experimental infection. Numerous microdendritic figures are seen between days 3-6 of infection, representing replication of the topically applied virus (Fig. 3). Dendrites disappear by day 6 and begin to reappear on day 11, after conjunctival necrosis releases a new wave of infectious virus particles. These secondary dendrites are larger, occasionally coalescing to form geographic and ameboid patterns, and are less numerous than those that appear initially. Histological studies demonstrate that corneal infection, in contrast to that of the

Figure l. Typical appearance of acute FHV-1 conjunctivitis. The conjunctiva is mildly swollen, severely hypere mic, and serous ocular discharge is present.

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Figure 2. Histologic appearance of FHV-1-infected conjunctiva on day 8 of experimental infection. The conjunctival epithelium has sloughed and an intense accumulation of polymorphonuclear and mononuclear inflammatory cells is present in the substantia propria. (H & E stain; X 320). (From Nasisse MP, Guy JS, Davidson MG, eta!: Experimental ocular herpesvirus infection in the cat. Sites of virus replication, clinical features, and effects of corticosteroid administration. Invest Ophthalmol Vis Sci 30:1758, 1989; with permission.)

conjunctiva, is characterized by replication of virus with relatively less cytopathic effect, and without an inflammatory cell response (Fig. 4). Corneal infection is associated with mild and transient superficial vascularization. Signs of ocular disease resolve coincident with the resolution of upper respiratory signs. Chronic and Secondary Infections The more important ocular manifestations of FHV-1 infection are those seen in adult cats that have presumably recovered from primary FHV-1 infection earlier in life. 4 • 7 • 36• 44 Although reinfection with a different strain· of FHV-1 is possible, it is probable that ocular infections in adult cats occur as a result of reactivation of latent virus. Such infections are properly termed recrudescent. In contrast to primary infection, signs of upper

Figure 3. Clinical appearance of rose bengal-stained microdendritic figures in the corneal epithelium of a cat during primary ocular FHV-1 infection.

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Figure 4. Histologic appearance of FHV-1-infected cornea on day 4 of experimental infection. Intracytoplasmic inclusion bodies are present; however, cytolysis is mild and inflammatory cells are absent. (H & E stain; X 415). (From Nasisse MP, Guy JS, Davidson MG, et al: Experimental ocular herpesvirus infection in the cat. Sites of virus replication, clinical features , and effects of corticosteroid administration. Invest Ophthalmol Vis Sci 30:1758, 1989; with permission.)

respiratory infection are absent and ocular manifestations are often unilateral. The signs of recrudescent infection may be confined to the conjunctiva or include variable degrees of keratitis. Adult FHV-1 conjunctivitis varies considerably with respect to severity. In many cases, mild conjunctival hyperemia and intermittent ocular discharge are the only signs. Significant conjunctival swelling is uncommon. Many cats display an accumulation of dried, brownish discharge at the medial canthus, but it is not known whether this finding is specific for herpesvirus infection. The clinical course in the adult infection may be weeks to many months, and is often recurrent. Corneal involvement in presumed recrudescent FHV-1 infection occurs as several distinct syndromes. In its simplest form, dendritic epithelial ulceration accompanies the conjunctivitis. Dendrites that persist for long periods of time may be accompanied by changes in the underlying stroma such as mild edema and superficial vascularization (Fig. 5). Dendritic lesions that enlarge to take on a map-like appearance are termed geographic. Very often, however, FHV-1 corneal infection has no suggestive clinical signs that distinguish it from other causes of corneal ulceration. Dendritic keratitis in adult forms of FHV-1 infection is thought to occur, as is that seen in primary infection, from viral replication in and destruction of epithelial cells.

Figure 5. Rose bengal-stained dendritic lesions in the cornea of a cat with naturally occurring FHV-1 infection. The epithelial lesions are accompanied by superficial stromal edema and vascularization. (From Nasisse MP, Guy JS: Feline ocular disease and the rhinotracheitis virus. Vet Med Report 1:155, 1989; with permission.)

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Stromal keratitis is the least common manifestation of corneal FHV-1 infection. Owing to its potential for causing vision-threatening c'o rneal scarring, however, it is the most significant manifestation of the disease. Stromal FHV-1 keratitis usually is seen associated with chronic epithelial ulceration and is recognized grossly by the presence of stromal edema and deep vascularization, and biomicroscopically by the presence of inflammatory cell infiltrates. The mechanism through which the stromal disease is mediated is unknown. Because FHV-1 does not normally replicate in keratocytes, stromal damage is unlikely to be a direct virus effect. Numerous experimental studies indicate that herpes simplex virus stromal keratitis is an immunopathologic event initiated by viral antigens that gain access to the corneal stroma, and a mediating role for cytotoxic T lymphocytes has been proposed. 25· 33• 35 Whatever the mechanism, chronic or recurrent episodes of FHV-1 stromal keratitis lead to progressive stromal collagen damage, fibrillar derangement, and eventually opacification (Fig. 6). Deep stromal ulceration and descemetoceles are occasionally associated with the presence of detectable FHV-1 in the ocular tear film . Whether or not the virus is instrumental in such cases is unclear. It seems unlikely that this virus is capable of inducing stromal melting. It is probable that in these cases the stromal melting is mediated by secondary bacterial infection, or that a primary bacterial ulceration has simply triggered the reactivation of latent virus with resultant shedding.

Associated Diseases Several important ophthalmic conditions of cats, while not necessarily caused specifically or exclusively by FHV-1, are sometimes seen associated with FHV-1 infection. Corneal sequestration is a unique disorder of the feline cornea that is characterized by chronic epithelial ulceration, stromal necrosis, and the accumulation of a still unidentified brown pigment within the corneal stroma. 23· 42 Corneal sequestration has been seen following chronic FHV-1 corneal infection in cats, raising the possibility that FHV-1 may be causative in some cases. It is this author's opinion that corneal sequestration is initiated, at least in part, by stromal damage, and that FHV-1 is but one of many potential causes. Symblepharon is the adhesion of conjunctiva to itself or to the cornea.

Figure 6. Corneal stromal scarring in chronic, FHV-1 keratitis. Corneal opacification is the result of damage to, and derangement of, the cornea's collage n lamellae.

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Figure 7. Symblepharon formation in a kitten, following chronic conjunctivitis associated with upper respiratory infection. The bulbar conjunctiva adheres to the central cornea.

In theory, any disease capable of significantly damaging the conjunctiva may predispose to symblepharon formation (Fig. 7). Considering the rapid and complete necrosis of conjunctival epithelium that can be seen in FHV-1 infection, this virus would seem ideally suited for initiating symblepharon formation. In the author's experience, the majority of feline symblepharon cases are associated with a previous upper respiratory and conjunctival infection historically compatible with FHV-1 infection. Entropion occurs relatively rarely in cats. Although it may be a primary, breed-related problem, many cases appear secondary to chronically painful ocular diseases such as viral keratitis. It is difficult to establish a cause and effect relationship in such cases, but so-called "spastic entropion" of cats appears to be a potential complication of the blepharospasm associated with chronic FHV-1 infection. It has been suggested that FHV-1 is a cause of keratoconjunctivitis sicca in cats. 41 This hypothesis is strengthened by results of a recent experimental study in which decreased tear production was seen in 5 of 10 cats with chronic ocular FHV-1 infection. 38 Although the mechanism of FHV-1 keratoconjunctivitis sicca remains speculative, it is probable that either ductal occlusion or lacrimal adenitis is responsible. In either case, decreased tear production associated with FHV-1 infection tends not to be permanent.

DIFFERENTIAL DIAGNOSIS OF FELINE HERPESVIRUS 1 INFECTION Feline herpesvirus 1 infection may be confused with any infectious disease of cats that manifests as conjunctivitis. Feline calicivirus is not a

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significant conjunctival pathogen. 27 • 52 • 53 Of the other conjunctival pathogens of cats, Chlamydia psittaci infection is most likely to mimic FHV-1 infection. There are, however, several major differences with respect to clinical presentation. Because C. psittaci is only mildly pathogenic to respiratory tissue, the presence of conspicuous respiratory disease excludes chlamydia as a consideration. 29 Ocular chlamydia infection is initially unilateral, as opposed to the bilateral involvement that typifies FHV-1 infection, at least during primary exposure. Chlamydia infection is further characterized by chemosis, with relatively less hyperemia than is seen in FHV-1 infection, and keratitis is typically not a component. For both FHV-1 and C. psittaci, however, these typical signs become less consistent with chronicity, necessitating laboratory diagnosis in such cases. Bacterial conjunctivitis is usually easy to distinguish from FHV-1 infection by its short clinical course and predictable response to broad spectrum antibiotics. Mycoplasma organisms have been found associated with conjunctivitis in cats, but they appear to exert little pathogenicity by themselves, given that experimental disease cannot be induced without some form of concurrent immunosuppression. 9 • 26 Like chlamydia, mycoplasma is not a corneal pathogen. Other organisms suggested to be potential conjunctival pathogens (reovirus, salmonella) appear to be of little significance in naturally occurring feline conjunctivitis. 15· 46 DIAGNOSIS OF FELINE HERPESVIRUS 1 INFECTION Clinical signs of FHV-1 ocular infection are generally only diagnostic during acute infections of young animals when suggestive ocular changes are accompanied by respiratory disease. The exception to this is the presence of dendritic corneal ulceration, which is nearly pathognomonic for FHV-1 infection. It must be emphasized, however, that FHV-1 corneal dendrites are subtle in appearance and will only be visible through careful examination using vital stains. Because corneal infection often does not result in the full-thickness loss of epithelium, fluorescein stain is poorly absorbed. Rose bengal is the stain of choice because it is absorbed by dead cells in the superficial epithelial layers. Virus isolation is considered the most sensitive means of detecting viral antigen in infected ocular secretions. Samples are optimally collected by rolling a swab moistened with virus transport media (minimal essential media containing antibiotics) in the conjunctival fornix. Because respiratory virus shedding may occur in recurrent FHV-1 infection, samples for virus isolation should also be collected from the oropharynx. Either cgtton swabs or commercial virus collection swabs are preferred; however, successful recovery of herpesviruses has been reported with the use of the commercial Culturette (Marion Scientific, Kansas City, MO). For most herpesviruses, samples stored at 4°C will not lose appreciable titer for up to a week. In the laboratory, aliquots of the sample are allowed to adsorb onto mono layers of Crandell-Reese feline kidney cells for 1 hour. Fresh medium is added to the cells, which are then incubated at 37°C in the pr~sence of 5% C0 2 and observed daily for characteristic FHV-1 cytopathic effect. The most practical laboratory test for diagnosis of FHV-1 infection is

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the fluorescent antibody test. Cells to be tested are collected by aggressive scraping with a Kimura platinum spatula from the conjunctival sac or, if there is corneal involvement, directly from the cornea. Slides are air dried and may be mailed to the appropriate laboratory. The fluorescent antibody test may be done by the direct method, in which fluorescein-labeled antiherpes antibody is reacted with the specimen, which is then viewed with a fluorescence microscope. Alternatively, the indirect method may be used, in which the specimen is first reacted with antiherpes antibody and the antigen-antibody complex is detected by then reacting the specimen with fluorescein-labeled antibody, directed against the animal species in which the primary antibody was generated. The indirect method is considered more sensitive and has the advantage of allowing different antigenantibody complexes to be detected with a single fluorescein conjugate. As with the direct method, a positive test is detected using a fluorescence microscope. Serology is of moderate value in supporting a diagnosis of FHV-1 infection in unvaccinated cats. Because FHV -1 titers are of low magnituide and tend not to rise predictably following re-exposure, the use of paired serum samples is of limited value. Based on the observation that at least 80% of recovered cats will become latently infected and 45% of these will shed virus spontaneously, however, serology has been suggested to be of value in identifying potential carriers of the virus. 16 Cytology of conjunctival scrapings is of little value in diagnosing FHV-1 infection. Although FHV-1 intranuclear inclusions are readily detected in histologic sections in acute infection, they are not seen in conjunctival scrapings with routinely used cytologic stains (Leukostat, Fisher Diagnostics, Orangeburg, NC). In addition, the neutrophilic inflammatory response seen in. conjunctival scrapings is hardly specific for FHV-1. The paradox of attempting laboratory diagnosis of FHV-1 is that when antigen detection tests are likely to be highly reliable, there is rarely a need for confirming a diagnosis. Both fluorescent antibody and virus isolation procedures, for example, are highly reliable for diagnosing FHV-1 during the acute primary infection, when antigen is plentiful. During these infections, however, clinical signs are generally incriminating. Unfortunately, during chronic and recurrent infections, when a confirmed diagnosis becomes important, both tests often yield negative results. Fluorescent antibody tests probably yield false-negative results because antigen-positive cells are present in low numbers. Virus isolation, likewise, often yields negative results in highly suspicious cases, possibly because secretory antibody neutralizes free virus. As a result of this dilemma, serious effort to diagnose FHV-1 infection should include fluorescent antibody tests, virus isolation, and serologic evaluation. TREATMENT OF OCULAR FELINE HERPESVIRUS 1 INFECTION The proper treatment of FHV-1 ocular disease varies, depending on the duration and tissues involved. In acute infections associated with upper respiratory signs, treatment is symptomatic and directed against secondary

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opportunistic organisms. If respiratory involvement is severe, a systemic broad spectrum antibiotic such as amoxicillin is indicated. The topical application of ophthalmic antibiotics four times daily is effective in preventing secondary infections while the virus infection runs its course. Tetracycline ophthalmic ointment (Terramycin, Pfizer Laboratories, New York, NY; Achromycin, Lederle Laboratories, Wayne, NJ) is the preferred agent because of its efficacy against C. psittaci and Mycoplasma sp. Specific antiviral therapy is generally indicated in cases with corneal involvement or those that are chronic or recurrent in nature. Three antiviral agents are available in ophthalmic formulation; these are idoxuridine (Stoxil, Smith Kline and French, Philadelphia, PA; Herpex, Allergan Pharmaceuticals, Irvine, CA), adenine arabinoside (Vira-A, Parke-Davis, Morris Plains, NJ), and trifluorothymidine (Viroptic, Burroughs Wellcome Research, Triangle Park, NC). Idoxuridine is a pyrimidine nucleoside analogue that exerts its antiviral effect primarily by competing with thymidine for incorporation into viral DNA. It thus inhibits virus assembly by resulting in the production of a defective genome. Adenine arabinoside decreases viral DNA synthesis by inhibiting viral DNA polymerase. Trifluorothymidine is a nucleoside analogue that becomes incorporated into viral DNA to subsequently inhibit virus-specific mRNA. 12 The relative potency of these drugs is trifluridine > > idoxuridine > adenine arabinoside. 37 Trifluridine is the drug of choice, particularly for cases with corneal involvement, owing to its superior ability to penetrate the cornea. 40 Treatment with idoxuridine ointment is recommended five times daily, and trifluridine solution, every hour for the first day, reduced to five times daily thereafter. Therapy should be continued until corneal lesions are healed or other clinical signs are inapparent. Ocular irritation may develop with any of these drugs, necessitating switching to a different compound. Because of their nonselective mode of action and potential for affecting eukaryotic cells, these drugs are limited to topical use in cats. Corticosteroids are contraindicated in most FHV-1 ocular infections because they delay corneal epithelialization and suppress local immune functions. In experimental infection, corticosteroids are associated with prolonged virus shedding and an exacerbation of clinical signs, and allow conjunctival and corneal epithelial infection to involve the corneal stroma. 38 It is the author's experience that the most difficult to manage naturally occurring infections are usually associated with a history of indiscriminate corticosteroid use. In chronic stromal keratitis, topical corticosteroids are beneficial to suppress the potentially scarring immune response to FHV-1 antigen, provided an antiviral medication is concurrently applied. Acyclovir (Zovirax, Burroughs Wellcome) is the current drug of choice for treating herpes simplex virus infections of humans. Because it is phosphorylated to the active compound only in the virus-infected cell, its antiviral activity is truly selective, allowing it to be used systemically. Based on the relative lack of sensitivity of FHV-1 to this drug in tissue culture (< 100 times the potency of trifluridine), it is unlikely to be beneficial for treating FHV-1 infections in cats. In vitro, the efficacy of _acyclovir against FHV-1 can be significantly increased if combined with recombinant inter-

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feron. 53 The suitability, however, of combination antiviral therapy in cats has yet to be established. We have identified several nontoxic antiviral agents that have exceptional activity against FHV-1 in tissue culture. Only time will tell, however, if they will become available in sufficient quantities to be of value in treating cats with FHV-1 infection. The immunosuppressive drug cyclosporin A has recently received much publicity as an effective anti-inflammatory agent for treating keratitis in small animals. 31 Cyclosporin A, however, has been shown experimentally to have a profoundly adverse effect on primary ocular viral infection. 34 Cyclosporin A may be a useful adjunct to antiviral therapy in cases where stromal keratitis is present.

SUMMARY Infection by FHV-1 is one of the most common ophthalmic diseases of domestic cats worldwide. Although the usual manifestations are conjunctivitis and keratitis, infection with this virus has been linked to a variety of other ophthalmic syndromes of cats, including keratoconjunctivitis sicca and corneal sequestration. Ocular FHV-1 infection of cats provides a significant diagnostic challenge to the practicing veterinarian because, in chronic cases, antigen detection tests often yield negative results. Although therapy for FHV-1 infections of cats is often difficult, the recent development of nontoxic antiviral drugs that demonstrate considerable efficacy against FHV-1 offers hope for improved therapeutic success in the future.

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